EXCLI Journal 2010;10:124-127 – ISSN 1611-2156 Received: August 17, 2011, published: August 18, 2011
Editorial: HEPATOTOXICITY P. Godoy Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany E-mail:
[email protected], Telephone: +49 231-1084-256, Fax: +49 231-1084-403 Research on hepatotoxicity has been intensified in recent years. This can be partly explained by large projects such as the German project Virtual Liver with more than 60 partners and the EU project NoTox where hepatocyte in vitro systems are applied and optimized. Hepatocyte cultures are well accepted in vitro systems in both pharmacology and toxicology (Hengstler et al., 2009a, b; Gebhardt et al., 2003; Hewitt et al., 2007; Godoy et al., 2010a, b; Meyer et al., 2011). However, following isolation from the liver and attachment to the matrix of a culture dish, primary hepatocytes undergo major alterations, often referred to as dedifferentiation (Godoy et al., 2009; Zellmer et al., 2010). In contradiction to previous concepts, hepatocyte dedifferentiation is not a passive process during which some function are lost but represents an active response of the hepatocytes to the novel environment. This involves focal adhesion kinase mediated activation of PI3k/Akt and Raf/Mek/Erk signalling. Further progress in the field of hepatotoxicity will depend on whether it will become possible to optimize culture conditions, so that cultivated hepatocytes better reflect the in vivo situation. It is therefore understandable that several of the recent publications have used hepatocytes in vitro, either to opitimize techniques, such as hypothermic preservation (Ostrowska et al., 2009) or to understand mechanisms of toxicity (e.g., Nakagawa et al., 2009; Arafa, 2009). A second cuttingedge topic is alcohol induced fatty liver which is addressed in two comprehensive articles (Zeng and Xie, 2009; Cederbaum et al., 2009) giving an overview over the key mechanisms, namely changes of the redox condition, transportation of lipids, altered fatty acid oxidation and the enhancement of lipogenesis. Table 1: Recent studies on hepatotoxicity
Key message
Reference
Benzylpenicillin (BPCN) is an efficient antidote against amanitins in human hepatocytes. Toxotrienol caused nodular hepatocellular hyperplasia (NHH) in a 104-week carcinogenicity study in rats. However NHH did not become neoplastic. Alcohol induced fatty liver is a frequent health problem without effective therapy. This review addresses relevant mechanisms, including changes of the redox condition, transportation impairment of lipids, compromised fatty acid oxidation and the enhancement of lipogenesis with a focus on PPAR α and SREBP-1. Adequate animal models to predict idiosyncratic drug induced liver injury (DILI) represent a cutting-edge topic in toxicology. This study shows that aodiaquine induces hepatotoxicity in mice only after depletion of glutathione.
Magdalan et al., 2009
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Tasaki et al., 2009
Zeng and Xie, 2009
Shimizu et al., 2009
EXCLI Journal 2010;10:124-127 – ISSN 1611-2156 Received: August 17, 2011, published: August 18, 2011
Table 1 (cont.): Recent studies on hepatotoxicity
Key message
Reference
The perfluorinated compounds PFOA and PFOS are widely distributed in the environment. The current study addresses possible interactions between both compounds in a human hepatoma cell line. However, only a summation effect was observed. Trichloroethylene is known to cause hepatocellular cancer in mice. Microarray analysis after oral administration of trichloroethylene revealed inhibition of the TGF-beta and activation of the MAPK signalling pathways. This review focusses on key mechanisms of alcohol-induced liver injury: production of reactive oxygen species, depletion of antioxidants and induction of CYP2E1. To study which of several hypothermic preservation media lead to optimal results, primary human hepatocytes were analyzed after storage at 4 °C for 24-72 h. The best results were obtained with HypoThermosol-FRS. A novel rapid and easy to handle thermoluminescence assay has been established to quantify oxidative stress in primary hepatocytes. This study presents the toxicokinetics of arsenic species in the liver of mice. This short editorial summarizes some current technical limitations of hepatocyte in vitro systems. Alpha-tocopherol ameliorates CCL4 induced liver necrosis and restores hepatic vitamin C concentration. Tert-butyl hydroperoxide drecreases intracellular glutathione and mitochondrial membrane potential in rat hepatocytes. Alpha-amanitin shows a biphasic course of toxicity in cultivated dog hepatocytes with inhibition of protein and urea synthesis, marginalization and condensation of nuclear chromatin in a first phase, and necrosis and apoptosis in a second phase. Using a rat hepatocarcinogenesis model the anthelmintic oxfendazole shows tumor promoting activity by generation of reactive oxygen species. Quinacrine inhibits CYP2E1 in rat livers and protects against genotoxicity by the CYP2E1 activated tobacco specific nitrosamine NNK. 4-Tert-octylphenol causes liver toxicity in rats. Carnitine deficiency increases susceptibility to paracetamol induced hepatotoxicity. The amphetamine-derived designer drugs MDMA and MBDB induce mitochondrial depolarization and cause DNA damage in rat hepatocytes.
Hu and Hu, 2009
Sano et al., 2009
Cederbaum et al., 2009; Hengstler et al., 2009a (editorial) Ostrowska et al., 2009
Schumann et al., 2009 Juárez-Reyes et al., 2009 Hengstler et al., 2009b Iida et al., 2009 Cervinková et al., 2009 Magdalan et al., 2009
Dewa et al., 2009
Karamanakos et al., 2009 Barlas and Aydoğan, 2009 Arafa, 2009 Nakagawa et al., 2009
Barlas N, Aydoğan M. Histopathologic effects of maternal 4-tert-octylphenol exposure on liver, kidney and spleen of rats at adulthood. Arch Toxicol 2009;83:341-9.
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EXCLI Journal 2010;10:124-127 – ISSN 1611-2156 Received: August 17, 2011, published: August 18, 2011
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Godoy P, Schug M, Bauer A, Hengstler JG. Reversible manipulation of apoptosis sensitivity in cultured hepatocytes by matrixmediated manipulation of signaling activities. Methods Mol Biol 2010a;640:139-55. Godoy P, Lakkapamu S, Schug M, Bauer A, Stewart JD, Bedawi E, et al. Dexamethasone-dependent versus -independent markers of epithelial to mesenchymal transition in primary hepatocytes. Biol Chem 2010b;391:73-83.
Magdalan J, Ostrowska A, Piotrowska A, Gomułkiewicz A, Szeląg A, Dziędgiel P. Comparative antidotal efficacy of benzylpenicillin, ceftazidime and rifamycin in cultured human hepatocytes intoxicated with α-amanitin. Arch Toxicol 2009;83: 1091-6.
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Meyer C, Godoy P, Bachmann A, Liu Y, Barzan D, Ilkavets I et al. Distinct role of endocytosis for Smad and non-Smad TGF-β signaling regulation in hepatocytes. J Hepatol 2011;55:369-78.
Hengstler JG, Godoy P, Bolt HM. The dilemma of cultivated hepatocytes. Arch Toxicol 2009b;83:101-3. 126
EXCLI Journal 2010;10:124-127 – ISSN 1611-2156 Received: August 17, 2011, published: August 18, 2011
Nakagawa Y, Suzuki T, Tayama S, Ishii H, Ogata A. Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its analogues, on isolated rat hepatocytes. Arch Toxicol 2009;83:69-80.
Shimizu S, Atsumi R, Itokawa K, Iwasaki M, Aoki T, Ono C et al. Metabolismdependent hepatotoxicity of amodiaquine in glutathione-depleted mice. Arch Toxicol 2009;83:701-7.
Ostrowska A, Gu K, Bode DC, Van Buskirk RG. Hypothermic storage of isolated human hepatocytes: a comparison between University of Wisconsin solution and a hypothermosol platform. Arch Toxicol 2009;83:493-502.
Tasaki M, Umemura T, Kijima A, Inoue T, Okamura T, Kuroiwa Y et al. Simultaneous induction of non-neoplastic and neoplastic lesions with highly proliferative hepatocytes following dietary exposure of rats to tocotrienol for 2 years. Arch Toxicol 2009; 83:1021-30.
Sano Y, Nakashima H, Yoshioka N, Etho N, Nomiyama T, Nishiwaki Y et al. Trichloroethylene liver toxicity in mouse and rat: microarray analysis reveals species differences in gene expression. Arch Toxicol 2009;83:835-49.
Zellmer S, Schmidt-Heck W, Godoy P, Weng H, Meyer C, Lehmann T et al. Transcription factors ETF, E2F, and SP-1 are involved in cytokine-independent proliferation of murine hepatocytes. Hepatology 2010;52:2127-36.
Schumann A, Bauer A, Hermes M, Gilbert M, Hengstler JG, Wilhelm C. A rapid and easy to handle thermoluminescence based technique for evaluation of carbon tetrachloride-induced oxidative stress on rat hepatocytes. Arch Toxicol 2009;83:709-20.
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